Process for preparing cinchophen



Patented Nov. 6, 1928.

UNITED STATES PATENT OFFICE.

RICHARD PASTERHACK, F BBOOKIIJYN, NEW YORK, ASSIGNOR TO CHARLES PFIZER & COMPANY, 01' BROOKLYN, NEW YORK, A CORPORATION OF NEW JERSEY.

rnociiss r03 rnnramne CINGHOPHEN.. i

No Drawing. Amilieatlon fled April 21,

This invention relatesto process for the manufacture of 2-phenyl-cinchoninic acid, commonly known asCinchophen, and has for its object to obtain a better yield than 5 is now obtained in the Doebner process, thereby diminishing side reactions tending to produce objectionable products.

Doebner et a1. (Annalen der Chemie, 242, p. 290, 1887) purport toobtain cinchophen by dissolvin equal molecules of pyruvic acid and benzal ehyde in absolute alcohol and adding 1 molecule of aniline dissolved in alcohol. The heat of reaction considerably raises the temperature and the mixture is then heated on a water bathfor three hours. In U. S. Patent 1,075,171, dated October 7, 1916, .cinchophen is made by gradually adding pyroracemic alcoholic solution of benzaldehyde aniline,

2 which is basically the Doebner reaction and tends to produce some objectionable side products.

I have studied the Doebner reaction and have found that the most favorable conditions for the formation of cinchophen and the suppression of side reactions tendingto produce substances such as diketo-pyrrol ine anil are obtained when aniline,benzaldehyd e, and an aqueous solution of pzruvic acid are simultaneously. run into iling alcohol.

The intermediate product reacts With a sec 7 I 3%!!! I l-i311 aniline Intermediate p toduct.

(pyruvic) acid to a boiling 0011mm O i MR0 1927. Serial No. 185,689.

Under such conditions, the formation of d1keto-pyrrolidine anil is reduced to an ins gnificant amount and an increased yield of cinchophen obtained. Without intending to limit myself thereby, I believe that in the Doebner react-ion there proceeds simultaneously wlth the formation of cinchophen one or more side reactions tending to formthe pyrrolidine anil above mentioned. I have further found that by the process above men- 40 tioned, these side reactions are materially suppressed and the formation of pyrrolidine anil above mentioned becomes insignificant.

In the Doebner process a primary product, -anilino-a-keto-phenyl-butyric-acid is first 4 formed. The reaction is as follows:

comm, 0.11.0110 OHS-00.0003

aniline benzaldehyde pyruvic acid coon ON O the reaction conditions, to a diketo-pyrrolidine or its anil, or to cinchophen. I

The. reaction in which the anil is formed co 7 Oh!!! Hi0 Intermediate product.

0nd molecule of aniline to'form the aiiil,

"l' iHaO dlketo-pyn'olidine anll.

d then by auto-oxidation and reduction of 2 molecules of 1 molecule is converted into cinchophen (the oxidized part) and the other (the reduced part) undergoing further unknown second- CODE Nm 'y-anillno-m-keto-phenyl-butyric acid.

COOH tn NEG Intermediate product.

The reduced product undergoes a number of secondary changes, which are unknown,

and result in gummy by-products whose formulas are unknown.

In m preferred process, I provide 293 parts 0% aqueous solution of pyruvic acid, and run this together with 93 parts of anilin and 106 parts of benzaldehyde simultaneously into suificient boiling 95% alcohol to hold the materials in solution. 1500 or more parts of alcohol will be sufficient. The preferred conditionis where the pressure is such as to give a temperature of about C. If ox gen is also supplied a still better yield is obtained. The parts given are approximately molecular weights. After further heating, the cinchophen separates out ary cha es resulting in gummy by-products. This reaction is as follows:

OOOH

i H H10 (L20 Intermediate product.

+ a' duced product.

cinchophen and is recovered and purified in desired man- I@ Where the pyr'uv1c acid is contaminated with pyrotartaric acid, suflicient excess of 25 anilin is used to neutralize it.

By this process the yield is increased 20% or more, and less anil formed.

I claim:

Process of preparing cinchophen consist- 30 Signed at 11 Bartett St, Brooklyn, in the as county of Kings and State of New York this 19th day of April A. D. 1927.

RICHARD PASTERNACK. 

